Due to the unpredictable nature of lupus nephritis (LN), it would be clinically valuable to discover a reliable biomarker for disease activity and progression. The aim of this study is to evaluate the role of anti-C1q antibodies, sCD40L and TWEAK in systemic lupus erythematosus (SLE) and their relation to disease activity and kidney involvement. This study included 47 patients with SLE, 28 with LN and 19 without LN, as well as, 20 healthy subjects as controls. All subjects underwent complete history, examination and estimation of disease activity index (SLEDAI) and renal SLEDAI. The following investigations were done for all subjects: anti-C1q antibodies, sCD40L, TWEAK and CD4/CD8 ratio, in addition to complete blood picture, ESR, kidney function tests, ANA, anti-ds DNA antibodies and C3, C4. Anti-C1q antibodies, sCD40L and TWEAK and anti-dsDNA were significantly higher in SLE patients than controls (P < 0.001 for each), while C3, C4 and CD4/CD8 ratio were significantly lower (P < 0.001, 0.05 and 0.001 respectively). In LN patients, anti-C1q antibodies, sCD40L and TWEAK were significantly higher than non LN patients (P < 0.001 for each). Anti-C1q antibodies, sCD40L and TWEAK correlated with traditional disease activity parameters (C3, C4, anti-dsDNA and SLEDAI) as well as rSLEDAI. Levels of serum TWEAK correlated with the development of LN in patients with SLE. We concluded that anti-C1q antibodies, sCD40L and TWEAK may be used as serum biomarkers for the assessment of disease activity and development of LN.